Dihydro ergocornine



3,270,020 l-CYANOETHYL 9,10 DIHYDRO ERGOCORNINE Albert Hofmann and FranzTroxler, both of Bottmingen,

Basel-Land, Switzerland, assignors, by mesne assignments, to FidelityUnion Trust Company, executive trustee No Drawing. Original applicationNov. 5, 1962, Ser. No. 235,559, now Patent No. 3,190,884, dated June 22,1965. Divided and this application Nov. 19, 1964, Ser.

2 Claims. or. 260-2855) in which R is an alkoxycarbonyl,dialkylcarbamoyl, hydroxyalkylcarbamoyl, dialkylureido oralkoxycarbonylamino radical, whereof the alkyl portion in each radicalcontains from one to four carbon atoms inclusive, a hydroxymethylradical or a carbonyl radical substituted with the tripeptide radical ofa natural ergot alkaloid of the peptide type, and a signifies theradical their acid addition salts, and pharmaceutical compositionscontaining, in addition to an inert carrier or vehicle, a compound Iand/ or an acid addition salt thereof.

The compounds I and their acid addition salts are produced by reacting acompound of the formula:

United States Patent 0 "'ice PM in Which R and x y have the abovesignificance, with acrylonitrile in the presence of a proton acceptorand, when an acid addition salt is required, salt formation is eifectedwith an organic or inorganic acid in a manner per se known.

Suitable acids for salt formation are, for example, hydrochloric,hydrobromic, hydriodic, sulfuric, citric, tartaric, succinic, maleic,malic, acetic, oxalic, benzoic, fumaric, gallic, hexahydrobenzoic,methanesulfonic and phosphoric acids.

The possibilities of obtaining variations of the lysergic acid moleculeand its derivatives, the most important of which are the natural ergotalkaloids and their 9,10- dihydr-o compounds, by chemical substitution,are very limited. Chemical conversions are difficult because of thetendency of the lysergic acid molecule to decompose due to itssusceptibility towards acids, bases and oxidation agents and even to theoxygen of the air and light and because of the ease with which isomersare formed. It was thus surprising to find that a cyanoethyl radicalcould readily be introduced into the 1-position of the lysergic acidmolecule.

The production of compounds I may, for example, be effected bydissolving a compound II in a suitable solvent such as dioxane andreacting it with acrylonitrile in the presence of a proton acceptor,e.g., sodium methylate, sodium ethylate or benzyl trimethylammoniumhydroxide, at room temperature or higher. Alcohols have been found to beunsuitable as solvents as they themselves react with acrylonitrile tosome extent. Acrylonitrile itself may also be used as the solvent andwhile the starting materials sometimes do not initially readily dissolvetherein they generally go into solution satisfactorily during the courseof the reaction.

For the purpose of isolation, the reaction mixture is preferably takenup and shaken in a binary solvent mixture, e.g., ether/ aqueous tartaricacid. The desired compound I is obtained from the acidic aqueous layer,isolation and purification being effected in accordance with knownmethods, e.g., by chromatography on aluminum oxide and/ orrecrystallization.

When acrylonitrile is used as the solvent and a solid alkali metalalcoholate as the proton acceptor, the latter may simply be filteredoif, the acrylonitrile evaporated and its polymerization productsseparated by taking up the residue in chloroform and chromatographingthe chloroform solution of the crude product.

The compounds I are solid at room temperature. They give positive VanUrks and Kellers color reactions in shades which dilfer from thecorresponding reactions of the starting materials.

The compounds I are useful as intermediates in the production ofpharmaceuticals or themselves have pharmaceutical proper-ties. Thepharmaceutical compounds have a serotonin-inhibiting action so that theymay be used in the treatment of psychic and rheumatic illnesses as wellas of allergies, in fiammations and migraine. l-cyanoethyl-D- lysergicacid (+)-butanolamide-(2') has been found to have an especially strongserotonin-inhibiting action. An elfective amount of a compound I iscombined with an inert carrier or vehicle to provide a pharmaceuticalcomposition in unit dosage form.

The term known as used herein designates a method described in theliterature on the subject or in actual use.

In the following non-limitative example all temperatures are stated indegrees centigrade. The melting points are corrected.

Example.-1-cyan0ethyl-9,1 O-dihydro-ergocornine 1.7 g. of9,IO-dihydro-ergocornine are heated to the boil at reflux with 10 cc. ofacrylonitrile and 0.2 g. of benzyltrimethyl-ammonium hydroxide for 2hours. The mixture is then shaken between a 1% aqueous tartaric acid andether and the crude bases, which have been isolated in the usual manner,are chromatographed on a column of 55 g. of aluminium oxide. The1-cyanoethyl=9,l0-dihydroergocornine is washed into the filtrate withabsolute chloroform and crystallizes from ethyl acetate in the shape ofleaflets containing ethyl acetate and having a melting point of l77179.[oc] =26 (c.=O.5 in pyridine). Kellers color reaction: weak pure blue.Van Urks color reaction: very weak grey-pink.

4 What is claimed is: 1. 1-cyan0ethyl-9,10-dihydro-ergocornine. 2. Anon-toxic pharmaceutically acceptable acid addition salt of1-cyanoethyl-9,lO-dihydro-ergocornine. 5

No references cited.

HENRY R. JILES, Acting Primary Examiner.

10 DONALD G. DAUS, Assistant Examiner.

1. 1-CYANOETHYL-9,10-DIHYDRO-ERGOCORNINE.